Abstract
The identification of Mycobacterium tuberculosis genes necessary for persistence in vivo provides insight into bacterial biology as well as host defense strategies. We show that disruption of M. tuberculosis membrane protein PerM (Rv0955) resulted in an IFN-γ-dependent persistence defect in chronic mouse infection despite the mutant’s near normal growth during acute infection. The perM mutant required increased magnesium for replication and survival; incubation in low magnesium media resulted in cell elongation and lysis. Transcriptome analysis of the perM mutant grown in reduced magnesium revealed upregulation of cell division and cell wall biosynthesis genes, and live cell imaging showed PerM accumulation at the division septa in M. smegmatis. The mutant was acutely sensitive to β-lactam antibiotics, including specific inhibitors of cell division-associated peptidoglycan transpeptidase FtsI. Together, these data implicate PerM as a novel player in mycobacterial cell division and pathogenesis, and are consistent with the hypothesis that immune activation deprives M. tuberculosis of magnesium.
Highlights
The success of Mycobacterium tuberculosis (Mtb) as a human pathogen is due to ability to persist in chronic infection, despite a robust adaptive immune response by the host
We show that a novel integral membrane protein, Rv0955/PerM, is essential for Mtb persistence during chronic mouse infection
The perM mutant required increased magnesium compared to wild type Mtb for replication and survival in culture and elongated in media with reduced magnesium concentration
Summary
Mtb infection is characterized by an acute phase of logarithmic bacterial growth lasting approximately three weeks, followed by a plateau in bacterial burden, persisting as a chronic infection. The transition from acute to chronic infection—from logarithmic bacterial growth to stable bacterial counts—results from the onset of the adaptive immune response and activation of host macrophages by CD4+ T cell-derived IFN-γ [1,2]. Several previously identified per mutants provide information about the processes required for survival in the activated macrophage following the onset of adaptive immunity. A per phenotype was observed for an Mtb mutant lacking isocitrate lyase-1, an enzyme involved in the glyoxylate shunt and methylcitrate cycle, as well as a mutant lacking the cholesterol transporter Mce, indicating that cholesterol and fatty acids are carbon sources required by Mtb to survive during chronic infection [9,10]
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